Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy.

Background/aims: Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation.

Methods: The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care.

Post-Amadori AGE inhibition as a therapeutic target for diabetic complications: a rational approach to second-generation Amadorin design.

Aminoguanidine and pyridoxamine (Pyridorintrade mark), two major inhibitors of advanced glycation end product (AGE) formation, have entered clinical trials for diabetic nephropathy. They share no structural similarity and are believed to inhibit AGE formation by entirely different mechanisms. Pyridoxamine is a post-Amadori AGE inhibitor-that is, an "Amadorin"-whereas aminoguanidine primarily scavenges reactive dicarbonyl precursors to AGEs.

Unusual susceptibility of heme proteins to damage by glucose during non-enzymatic glycation.

Glucose modifies the amino groups of proteins by a process of non-enzymatic glycation, leading to potentially deleterious effects on structure and function that have been implicated in the pathogenesis of diabetic complications. These changes are extremely complex and occur very slowly. We demonstrate here that hemoglobin and myoglobin are extremely susceptible to damage by glucose in vitro through a process that leads to complete destruction of the essential heme group.

Modification of proteins in vitro by physiological levels of glucose: pyridoxamine inhibits conversion of Amadori intermediate to advanced glycation end-products through binding of redox metal ions.

Hyperglycemic conditions of diabetes accelerate protein modifications by glucose leading to the accumulation of advanced glycation end-products (AGEs). We have investigated the conversion of protein-Amadori intermediate to protein-AGE and the mechanism of its inhibition by pyridoxamine (PM), a potent AGE inhibitor that has been shown to prevent diabetic complications in animal models. During incubation of proteins with physiological diabetic concentrations of glucose, PM prevented the degradation of the protein glycation intermediate identified as fructosyllysine (Amadori) by 13C NMR using [2-13C]-enriched glucose.

Reflections on Edsall's carbonic anhydrase: paradoxes of an ultra fast enzyme.

John Edsall's investigations of human erythrocyte carbonic anhydrase, a zinc metalloenzyme that powerfully catalyzes the reversible hydration of carbon dioxide, highlighted a conundrum regarding the correct hydration product. The measured kinetic parameters could not be reconciled with the choice of carbonic acid, since its bimolecular recombination rate with enzyme would exceed the diffusion limit. The alternate choice of bicarbonate obviated the recombination rate problem but required that the active site deprotonation exceed the diffusion-limited maximum rate by an even greater extent.